HemePipeline Review

FDA Grants Breakthrough Therapy Designation to Magrolimab for MDS Treatment

The FDA has granted breakthrough therapy designation to magrolimab for the treatment of newly diagnosed myelodysplastic syndrome (MDS), according to Gilead Sciences, the developer of the agent.¹

The designation for magrolimab was granted based on positive results observed in an ongoing phase 1b study, which is evaluating magrolimab in combination with azacitidine (Onureg) in previously untreated intermediate-, high-, and very high-risk MDS.

According to data presented at the 2020 European Hematology Society Congress, 30 (91%) of 33 evaluable patients treated with magrolimab plus azacytidine achieved an objective response, including 42% who achieved a complete remission (CR).² After 6 months or more of follow-up, the observed CR rate rose to 56%.

Median time to initial response was 1.9 months, and the median duration of response has not yet been reached after a median follow-up of 5.8 months.

The combination of magrolimab plus azacitidine was found to be generally well tolerated. Common treatment-related adverse events (TRAEs) or AEs of interest were anemia (44%), fatigue (18%), infusion reaction (18%), neutropenia (8%), and thrombocytopenia (5%). No maximum tolerated dose was reached and no patients with MDS discontinued treatment due to a TRAE.

Magrolimab is an investigational agent and has not been approved anywhere globally. However, the first-in-class, investigational anti-CD47 monoclonal antibody has been granted fast track designation by the FDA for the treatment of MDS, acute myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma.

REFERENCES

1. Gilead’s Magrolimab, an investigational anti-CD47 monoclonal antibody, receives FDA breakthrough therapy designation for treatment of myelodysplastic syndrome. News release. Gilead; September 15, 2020. Accessed September 15, 2020. http://investors.gilead.com/news-releases/news-release-details/gileads-magrolimab-investigational-anti-cd47-monoclonal-antibody

2. Sallman DA, Asch A, Al-Malki M, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Abstract presented at: 25th European Hematology Society Congress; June 11-21, 2020. Abstract S187.

Efficacy of 5- and 10-Day Decitabine Schedules Not Different in Elderly Patients With AML

A randomized phase 2 trial of decitabine schedules in older patients with newly diagnosed acute myeloid leukemia (AML) found that efficacy and safety did not differ between a 5-day or 10-day decitabine schedule. The study results, published in The Lancet Haematology, also did not identify a subgroup that benefited preferentially from either schedule of decitabine.

Eligible patients had AML and were 60 years or older, but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The composite primary end points were complete remission (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete hematological recovery (CRi), achieved at any time and assessed by intention to treat.

Seventy-one patients were enrolled in the study, including 28 who received decitabine for 5 days and 43 for 10 days. Total follow-up was 38.2 months, with a median overall survival (OS) of 5.5 months (interquartile range, 2.1-11.7) in the 5-day group and 6.0 months (1.9-11.7) in the 10-day group. One-year OS was 25% in both groups. Overall, the primary end point was achieved in comparable proportions of patients in the 2 treatment cohorts: 12 (43%) of 28 in the 5-day schedule group (95% CI, 26%-60%); and 17 (40%) of 43 in the 10-day schedule group, (95% CI, 26%-54%); P = .78; difference, 3%; 95% CI, –21% to 27%. When stratified by cytogenetics, de novo vs secondary or therapy-related AML, or TP53mut status, CR, CRp, CRi, and OS did not differ between groups.

The most common grade 3/4 adverse events (AEs) observed were neutropenic fever (7 patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (5 [18%] and 16 [37%], respectively). One patient (4%) in the 5-day group died from sepsis in correlation with neutropenic fever, infection, and hemorrhage, while 6 patients (14%) in the 10-day group died from infection.

REFERENCE

1. Short NJ, Kantarjian HM, Loghavi S, et al. Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial. Lancet Haematol. 2019;6(1):e29-e37. doi:10.1016/S2352-3026(18)30182-0

Treatment-Free Remission Not Impaired by Low-Dose TKIs for Patients With CML

Long-term treatment-free remission was not impaired by low-dose tyrosine kinase inhibitor (TKI) regimens before TKI cessation in patients with chronic myeloid leukemia (CML), according to a retrospective study published in Cancer.

Results from the study demonstrated that with a median follow-up of 61.5 months, treatment-free remission was 56.8% at 12 months in the full-dose TKI group and 80.8% in the low-dose group. Treatment-free remission at 60 months was 47.5% and 58.8%, respectively. Dose reduction was 50% or greater for 65.4% of patients in the low-dose group, with 61.5% of patients receiving second-generation TKIs.

Investigators retrospectively analyzed 77 patients with CML who discontinued their treatments with TKIs. Of that group, 26 patients were managed with low-dose TKIs before stopping treatment. The loss of major molecular response was considered a trigger for restarting therapy.

A median time to molecular recurrence from TKI discontinuation of 6.2 months was observed for the entire cohort, and all patients achieved major molecular response after resuming TKI therapy. Overall, the results appear independent of both dose reduction and potential pretreatment with interferon-α.

REFERENCE

1. Cayssials E, Torregrosa-Diaz J, Gallego-Hernanz P, et al. Low-dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment-free remission in chronic myeloid leukemia patients: results of a retrospective study. Cancer. 2020;126(15):3438-3447. doi:10.1002/cncr.32940

Phase 2 CLOVER-1 Study Shows Promise for Patients With Triple-Class Refractory Multiple Myeloma

Data from the phase 2 CLOVER-1 study, evaluating the efficacy and safety of CLR 131, showed a clinically meaningful 40% overall response rate (ORR) in a subset of patients with refractory multiple myeloma deemed triple-class refractory who received a total administered dose of 60 mCi or greater.

CLR 131 is a small-molecule phospholipid-drug conjugate developed by Cellectar Biosciences designed to provide targeted delivery of iodine-131 directly to cancer cells. The subset of patients in the CLOVER-1 study who achieved the 40% ORR (n = 6) represents patients who were found to be triple-class refractory and were enrolled in part A dose-exploration portion of the study, as well as additional patients enrolled in the part B expansion cohorts from March through May 2020. All patients being enrolled in part B of the study are required to be triple-class refractory.

Consistent with data released in February 2020, patients receiving more than 60 mCi of CLR 131 have exhibited strong responses. Cellectar Biosciences indicated that patients continue to tolerate CLR 131 well, with the most common and almost exclusive treatment-emergent adverse events (AEs) being cytopenias. Importantly, no unexpected AEs have been
reported.

REFERENCE

1. Cellectar reports data on CLR 131 phase 2 CLOVER-1 study in triple class refractory multiple myeloma patients. News release. Cellectar; September 9, 2020. Accessed September 16, 2020. https://www.globenewswire.com/news-release/2020/09/09/2090856/0/en/Cellectar-Reports-Data-on-CLR-131-Phase-2-CLOVER-1-Study-in-Triple-Class-Refractory-Multiple-Myeloma-Patients.html

Study of Adherence Interventions in Children With ALL Does Not Meet Primary End Point

An analysis of the effect of a daily text message and directly supervised therapy intervention on oral mercaptopurine (Purixan) adherence in children with acute lymphoblastic leukemia (ALL) did not meet its primary end point, according to a study published in JAMA Network Open.

Investigators analyzed the adherence rates of 444 children, randomized 1:1 to either education alone or the intervention package, which consisted of education plus personalized daily text messages to prompt directly supervised therapy, and found no difference in the proportion of patients with adherence rates of 95% or higher. However, an exploratory analysis revealed that children 12 years and older with a baseline adherence of less than 90% had a higher mean adherence in the intervention group.

Suboptimal adherence to oral mercaptopurine treatment in children with ALL is known to increase the risk of relapse in those patients. A commonly cited barrier to adherence is forgetfulness, which generally must be overcome with parental vigilance.

REFERENCE

1. Bhatia S, Hageman L, Chen Y, et al. Effect of a daily text messaging and directly supervised therapy intervention on oral mercaptopurine adherence in children with acute lymphoblastic leukemia: a randomized clinical trial. JAMA Netw Open. 2020;3(8):e2014205. doi:10.1001/jamanetworkopen.2020.14205